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WO2007113644A2 - Nouveaux inhibiteurs d'hdac - Google Patents

Nouveaux inhibiteurs d'hdac Download PDF

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Publication number
WO2007113644A2
WO2007113644A2 PCT/IB2007/000853 IB2007000853W WO2007113644A2 WO 2007113644 A2 WO2007113644 A2 WO 2007113644A2 IB 2007000853 W IB2007000853 W IB 2007000853W WO 2007113644 A2 WO2007113644 A2 WO 2007113644A2
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WIPO (PCT)
Prior art keywords
amino
methyl
compound
oxooctanoyl
ethyl
Prior art date
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Ceased
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PCT/IB2007/000853
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English (en)
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WO2007113644A3 (fr
Inventor
Akella Satya Surya Visweswara Srinivas
Virendra Kachhadia
Kasinathan Mathiyazhagan
Sathya Narayana Thara
Lakshmanan Manikandan
Sriram Rajagopal
Gaddam Om Reddy
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Orchid Research Laboratories Ltd
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Orchid Research Laboratories Ltd
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Publication of WO2007113644A2 publication Critical patent/WO2007113644A2/fr
Anticipated expiration legal-status Critical
Publication of WO2007113644A3 publication Critical patent/WO2007113644A3/fr
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D277/82—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen

Definitions

  • the present invention relates to novel compounds of the general formula (I), having histone deacetylase (HDAC) inhibiting enzymatic activity, their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts and compositions, metabolites and prodrugs thereof.
  • HDAC histone deacetylase
  • the present invention more particularly provides novel compounds of the general formula (I).
  • the present invention also provides a process for the preparation of the above said novel compounds of the general formula (I), their derivatives, analogs, stereoisomers, polymorphs, hydrates, solvates, pharmaceutically acceptable salts and compositions, metabolites and prodrugs thereof.
  • novel compounds (I) of the present invention are useful for the treatment of cancer, which is one of the leading causes of death in the present society.
  • a great deal of effort has been underway to treat various forms of cancer for decades and until recently, chemoprevention of cancer is receiving its due share of attention.
  • HDACs histone deacetylases
  • HDACs histone deacetylases
  • HDACs histone deacetylases
  • RPD 3 class I includes HDAC 1, 2, 3, 8, and 11
  • Hda 1 class II includes HDAC 4, 6, 7, 9, and 10
  • All of the HDACs have a highly conserved zinc dependent catalytic domain.
  • Transcriptional regulation is a major event in cell differentiation, proliferation and apoptosis. Transcriptional activation of a set of genes determines cell destination and for this reason transcription is tightly regulated by a variety of factors.
  • One of its regulatory mechanisms involved in the process is an alteration in the tertiary structure of DNA, which affects transcription factors to their target DNA regimens.
  • Nucleosomal integrity is regulated by the acetylating status of the core histone, with the result being permissiveness to transcription.
  • the acetylating status of the histone is governed by the balance of activities of the histone acetyl transferase (HAT) and histone deacetylase (HDAC).
  • HAT histone acetyl transferase
  • HDAC histone deacetylase
  • HDAC inhibitors have been found to arrest growth and apoptosis in several types of cancer cells, including colon cancer, t-cell lymphoma and erythroleukemic cells. (J. E. Bolden, M. J. Peart, R. W. Johnstone, Nature Review Drug Discovery, 5, 2006, 769-784)
  • HDAC inhibitors are promising reagents for cancer therapy as effective inducers of apoptosis.
  • HDAC inhibitors Several structural classes of HDAC inhibitors have been identified and are reviewed in Marks, P.A. et al., J. Natl. Cancer Inst., 92, (2000), 1210-1215. More specifically WO 98/55449 and US patent 5,369,108 report alkanoyl hydroxamates with HDAC inhibitory activity.
  • the present invention relates to potentially pharmaceutical compositions and in particular to new molecules as active ingredients, that are used in particular as anticancer agents.
  • Compounds of the general formula (I) or pharmaceutically acceptable salts thereof according to the present invention have an ability of inhibiting histone deacetylating enzyme and of inducing differentiation and are useful as therapeutic or ameliorating agent for diseases that are involved in cellular growth such as malignant tumors, autoimmune diseases, skin diseases, infections etc.
  • Cy is Cyclyl group (C 3-2 O carbocyclyl, C 3-20 heterocyclyl or C 5-20 aryl and is optionally substituted)
  • Qi represents covalent bond or cyclyl leader group (Ci -7 alkylene, Ci -7 alkylene-X- Ci -7 alkylene, -X- Ci -7 alkylene, or Ci -7 alkylene-X-), wherein X is -O- or -S- and is optionally substituted;
  • This invention pertains to pharmaceutical compositions containing such compounds and their use both in vitro and in vivo, to inhibit HDAC and in the treatment of conditions mediated by HDAC, cancer, proliferative conditions, psoriasis, etc.
  • A is an aryl group
  • Qi is an aryl leader group having a backbone of at least two carbon atoms
  • J is an amide linkage selected from:
  • Y is R 1 NHC(O) or R 2 C(O)NR 3 ;
  • R 2 is an optionally substituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aryloxy, arylalkyloxy, or alkyl, where the aryl, etc. cyclic
  • R 3 is H, alkyl or C(O)R 4 ;
  • R 4 is an optionally substituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aryloxy, arylalkyloxy, or alkyl, where the aryl, etc.
  • cyclic systems can be bicyclic; R is (CH 2 ) n or CH(A-R 5 ) ⁇ (CH 2 ) n- i; n is 3-8; A is NH, O, S, CH 2 , NHCO, or NHCO 2 ; and R 5 is an optionally substituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or alkyl, where the aryl, etc. cyclic systems can be
  • Histone acetylation and deacetylation play an essential role in modifying chromatin structure and regulating gene expression in eukaryotic cells. Hyperacetylated histones are generally found in transcriptionally active genes and in transcriptionally silent
  • HATs histone acetyl transferases
  • HDACs histone deacetylases
  • HDAC inhibitors such as Trichostatin A (TSA), Trapoxin (TPX), Suberoylanilide hydroxamic acid (SAHA), Sodium butyrate (NaB), Sodium valproate (VPA), Cyclic hydroxamic acid containing peptides (CHAPs), Depsipeptide FK-228 and MS-275 (Benzamide) can - de-repress these genes, resulting in antiproliferative effects in vitro and anti tumor effects in vivo.
  • TSA Trichostatin A
  • TPX Trapoxin
  • SAHA Suberoylanilide hydroxamic acid
  • NaB Sodium butyrate
  • VPA Sodium valproate
  • CHAPs Cyclic hydroxamic acid containing peptides
  • Depsipeptide FK-228 and MS-275 Benzamide
  • the present invention relates to novel substituted HDAC inhibitors of the
  • A represents substituted or unsubstituted groups selected from aryl, aralkyl, heterocyclyl, heteroaryl, ' heteroarylmethyl, benzofused heteroarylmethyl and benzofused heteroaryl; wherein X represents oxygen, sulphur or NH; wherein B represents the substituted or unsubstituted hydroxamic acid group, the thioate group, the heterocyclyl groups and n is an integer in the range of 1 to 7.
  • the present invention relates to novel substituted HDAC inhibitors of the general formula (I),
  • suitable groups represented by A are substituted or unsubstituted groups selected from aryl groups such as phenyl, naphthyl and the like; arylalkyl groups such as, phenylmethyl, naphthylmethyl, and the like; heterocyclyl groups such as pyrrolidinyl, thiazolidinyl, oxazolidinyl, morpholinyl, thiomorpholinyl, piperidinyl,
  • heteroaryl groups such as pyridyl, thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, isooxazolyl, oxadiazolyl, triazolyl, thiadiazolyl, tetrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl and the like; benzofused heteroaryl groups such as indolyl, indolinyl, benzothiazolyl, quinolinyl, quinoxalinyl, quinazolinyl, acridinyl, phenazinyl, pteridinyl, phenoxazinyl, phenothiazinyl, carbazolyl and the like; heteroarylalkyl groups such as pyridylmethyl, thienylmethyl, furylmethyl, pyrrolylmethyl, oxazolyl, thiazolyl
  • the group X is represented by oxygen, sulphur or NH.
  • B represents the substituted or unsubstituted hydroxamic acid group (O-acyl, N- acyl, O-alkyl, N-alkyl, O-pivaloyl, O-alkoxy carbonyl, N-alkoxy carbonyl, O-aralkyl, both or either of any two combination), thioate group such as ethane thioate and the like, heterocyclyl groups such as morpholine and thiomorpholine and the like.
  • n is an integer in the range of 1 to 7.
  • Suitable groups substituted on A may be selected from halogens such as fluorine, chlorine, bromine or iodine, hydroxy, nitro, cyano, azido, nitroso, amino, hydrazine, hydrazide, hydroxamate, formyl, alkyl, haloalkyl, haloalkoxy, cycloalkyl, aryl, alkoxy, aryloxy, acyl, acyloxy, acyloxyacyl, heterocyclyl, heteroaryl, monoalkylamino, dialkylamino, acylamino, alkylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclylcarbonyl, arylsulfonyl, alkylsulfinyl, arylsulfinyl, alkylthio, arylthio, sulfamoyl, alkoxyalkyl groups and carboxylic acids or its derivative
  • a which is a cyclic ring represents substituted or unsubstituted 5 to 10 membered ring systems, and also the rings may be monocyclic or bicyclic, saturated 5 or partially saturated or aromatic containing 1 to 4 hetero atoms selected from O, S, N and the like.
  • alkyl as used herein, means a straight or branched chain 10 hydrocarbon containing from 1 to 10 carbon atoms.
  • Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t- butyl and the like.
  • alkoxy as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • Representative 15 examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, iso- propoxy, ?-butoxy and the like.
  • alkoxycarbonyl as used herein, includes groups such as methoxy carbonyl, ethoxy carbonyl and the like.
  • analog includes a compound, which differs from the parent structure 20 by one or more C, N, O or S atoms.
  • a compound in which one of the N atoms in the parent structure is replaced by an S atom is an analog of the former.
  • stereoisomer includes isomers that differ from one another in the way the atoms are arranged in space, but whose chemical formulas and structures are otherwise identical.
  • Stereoisomers include enantiomers and diastereoisomers.
  • tautomers include readily interconvertible isomeric forms of a compound in equilibrium. The keto- enol tautomerism is an example.
  • polymorphs include crystallographically distinct forms of compounds with chemically identical structures.
  • pharmaceutically, acceptable solvates includes combinations of solvent 30. molecules with molecules or ions of the solute compound.
  • the term derivative refers to a compound obtained from a compound according to formula (I), an analog, tautomeric form, stereoisomer, polymorph, hydrate, pharmaceutically acceptable salt or pharmaceutically acceptable solvate thereof, by a simple chemical process converting one or more functional groups, such as, by oxidation, hydrogenation, alkylation, esterification, halogenation, and the like.
  • salts of the present invention include alkali metals like Li, Na, and K, alkaline earth metals like Ca and Mg, salts of organic bases such as diethanolamine, ⁇ -phenylethylamine, benzylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, choline hydroxyethylpiperidine, and the like, ammonium or substituted ammonium salts, aluminum salts. Salts also include amino acid salts such as glycine, alanine, cystine, cysteine, lysine, arginine, phenylalanine, guanidine etc.
  • Salts may include acid addition salts where appropriate, which are, sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, succinates, palmoates, methanesulphonates, tosylates, benzoates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like.
  • Pharmaceutically acceptable solvates may be hydrates or comprising other solvents of crystallization such as alcohols.
  • Particularly useful compounds according to invention include:
  • Compound (Ia) and the reagent used in the Step-V are secondary amines, wherein R 1 , R 2 and R 3 , R 4 may be same or different and are selected from alkyl, aryl, or R 1 and R 2 , and also R 3 and R 4 form, together with the nitrogen to which they are attached, a cyclic group selected from azetidino, pyrrolidino, piperidino, piperazino and morpholino, wherein the said cyclic group may be optionally substituted; A represents substituted or unsubstituted groups selected from aryl, aralkyl, heterocyclyl, heteroaryl, heteroarylmethyl, benzofused heteroaryl and benzofused heteroarylmethyl; and X represents oxygen, sulphur or NH
  • the compound of formula (Ic) is reduced to the compound of formula (Id) using 10% Pd/C.
  • the compound of formula (Id) was converted to the compound of formula (Ie) by reaction with halo alkanoylchloride.
  • the compound of the formula (Ie) was treated with potassium thioacetate in the presence of a suitable base like triethylamine, NaOH, KOH, pyridine, or potassium carbonate i.e. Step IV to get the compounds of the formula (If) and the compound of the formula (Ie) is also further reacted with either primary or secondary amines in the presence of a suitable base like triethylamine, NaOH, KOH, pyridine, or potassium carbonate i.e.
  • Step V to get the compounds of the formula (1). It is appreciated that in any of the above-mentioned reactions any reactive functional group in the substrate molecule may be protected according to the conventional chemical practice. Suitable protecting groups in any of these reactions are those used conventionally in the art and the methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected.
  • salts of the present invention include alkali metals like Li, Na, and K, alkaline earth metal like Ca and Mg, salts of organic bases such as diethanolamine, ⁇ -phenylethylamine, benzylamine, piperidine, morpholine, pyridine, hydroxyethylpyrrolidine, hydroxyethylpiperidine, choline and the like, ammonium or substituted ammonium salts, aluminum salts. Salts also include amino acid salts such as glycine, alanine, cystine, cysteine, lysine, arginine, phenylalanine, guanidine etc.
  • Salts may include acid addition salts where appropriate like sulphates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartarates, maleates, citrates, succinates, palmoates, methanesulphonates, tosylates, benzoates, trifluoroacetates, salicylates, hydroxynaphthoates, benzenesulfonates, ascorbates, glycerophosphates, ketoglutarates and the like.
  • Compounds of the formula (I) may form solvates of DMF, hydrates and the like.
  • compounds of the invention may contain groups that may exist in tautomeric forms and though one form is named, described, displayed and/or claimed herein, all the forms are intended to be inherently included in such name, description, display and/or claim.
  • stereoisomers of the compounds forming part of this invention may be prepared by using reactants in their single enantiomeric form, in the process wherever possible or by conducting the reaction in the presence of reagents or catalysts in their single enantiomeric form or by resolving the mixture of stereoisomers by conventional methods.
  • Some of the preferred methods include use of microbial resolution, resolving the diastereomeric salts formed with chiral acids such as mandelic acid, camphorsulfonic acid, tartaric acid, lactic acid, and the like wherever applicable or by using chiral bases such as brucine, cinchona alkaloids, their derivatives and the like.
  • Prodrugs of the compounds of formula (I) are also contemplated by this invention.
  • a prodrug is an active or inactive compound that is modified chemically through in-vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of the invention following administration of the prodrug to a patient.
  • the suitability and techniques involved in making/using prodrugs are well known to those skilled in the art.
  • polymorphs of the compounds of the general formula (I), forming part of this invention may be prepared by crystallization of the compounds of formula (I) under different conditions. For example, using different commonly used solvents, or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Heating or melting the compounds followed by cooling gradually or immediately, one can also obtain polymorphs.
  • the presence of polymorphs may be determined by solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry and powder X-ray diffraction or other such techniques.
  • solvates of the compounds of the formula (I) forming part of this invention may be prepared by conventional methods such as dissolving the compounds of the formula (I) in solvents such as water, methanol, ethanol, mixture of solvents such as acetone: water, dioxane:water, N 9 N- dimethylformamide:water and the like, preferably water and recrystallization by using different crystallization techniques.
  • solvents such as water, methanol, ethanol, mixture of solvents such as acetone: water, dioxane:water, N 9 N- dimethylformamide:water and the like, preferably water and recrystallization by using different crystallization techniques.
  • the present invention also provides a pharmaceutical composition, containing one or more of the compounds of the general formula (I) as defined above, their derivatives, analogs, tautomeric forms, stereoisomers, polymorphs, hydrates, metabolites, prodrugs, pharmaceutically acceptable salts, pharmaceutically acceptable solvates in combination with the usual pharmaceutically employed carriers, diluents and the like, useful for the treatment of cancer, psoriasis, proliferative conditions and conditions mediated by HDAC .
  • the derivatives provided by the present invention can be employed as pharmaceutical compositions, for example, in the form of pharmaceutical compositions containing the derivatives together with appropriate, pharmaceutically acceptable carriers.
  • the products in accordance with the invention can be administered, for example, perorally, such as in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions, or rectally, such as in the form of suppositories, etc.
  • the compositions may be sterilized and may contain auxiliary agents generally employed in the pharmaceutical art, such as sodium hydrogen carbonate, citric acid, propylene glycol, tween 80, etc.
  • the compounds can be used orally or parenterally.
  • compositions containing these compounds can be prepared using conventional procedures familiar to those skilled in the art, such as by combining the ingredients into a dosage form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and if desired, the usual pharmaceutical adjuvants.
  • the amount of the active ingredient in the composition may be less than 70% by weight.
  • Such compositions typically contain from 1 to 25%, preferably 1 to 15% by weight of active compound, the remainder of the composition being pharmaceutically acceptable carriers, diluents, excipients or solvents.
  • the pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions and the like, may contain flavorants, sweeteners etc. in suitable solid or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions.
  • suitable pharmaceutically acceptable carriers include solid fillers or diluents and sterile j aqueous or organic solutions.
  • the active compound will be present in such pharmaceutical compositions in the amounts sufficient to provide the desired dosage in the range as described above.
  • the compounds can be combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like.
  • the pharmaceutical compositions may, if desired, contain additional components such as flavorants, sweeteners, excipients and the like.
  • the compounds can be combined with sterile aqueous or organic media to form injectable solutions or suspensions.
  • injectable solutions or suspensions For example, solutions in sesame or peanut oil, aqueous propylene glycol and the like can be used, as well as aqueous solutions of water-soluble pharmaceutically-acceptable acid addition salts or alkali or alkaline earth metal salts of the compounds.
  • the injectable solutions prepared in this manner can then be, administered intravenously, intraperitoneally, subcutaneously, or intramuscularly, with intramuscular administration being preferred in humans.
  • the effective dose for treating a particular condition in a patient may be readily determined and adjusted by the physician during treatment to alleviate the symptoms or indications of the condition or disease.
  • a daily dose of the active compound in the range of about 0.01 to 1000 mg/kg of body weight is appropriate for administration to obtain effective results.
  • the daily dose may be administered in a single dose or divided into several doses. In some cases, depending upon the individual response, it may be necessary to deviate upwards or downwards from the initially prescribed daily dose.
  • Typical pharmaceutical preparations normally contain from about 0.2 to about 500 mg of active compound of formula I and/or its pharmaceutically active salts or solvates per dose.
  • the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds of the invention or other agents.
  • the therapeutic agents can be formulated as separate compositions that are given at the same time or different times, or the therapeutic agents can be given as a single composition.
  • the term "therapeutically effective amount” or “effective amount” refers to that amount of a compound or mixture of compounds of Formula (I) that is sufficient to effect treatment, when administered alone or in combination with other therapies to a mammal in need of such treatment.
  • animal as used herein is meant to include all mammals, and in particular humans. Such animals are also referred to herein as subjects or patients in need of treatment.
  • the therapeutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the particular compound of Formula (I) chosen, the dosing regimen to be followed, timing of administration, the manner of administration and the like, all of which can readily be determined by one of ordinary skilled in the art.
  • treatment means any treatment of a disease in a mammal, including: a) Preventing the disease, that is, causing the clinical symptoms of the disease not to develop; b) Inhibiting the disease, that is, slowing or arresting the development of clinical symptoms; and/or c) Relieving the disease, that is, causing the regression of clinical symptoms.
  • Step: 1 Preparation of ethyl 2-amino-l,3-benzothiazole-6-carboxylate.
  • reaction mixture was later poured into ice water to give a white precipitate, which was filtered, washed consecutively with hexane (100ml x 2), and dichloromethane (25ml) to give the title compound as a white colored solid (0.37g, 90% yield) with m.p.: 168-171 0 C.
  • reaction mixture was poured into ice water to give a white precipitate, which was filtered, washed consecutively with hexane (15OmL x 2) and chloroform (5OmL) to give the product (0.33g, 78.7% yield) as a white colored solid.
  • 6-bromo-N-[5-(morpholin-4-ylcarbonyl)-2-furyl]hexanamide(3.Og, 8mmol) was dissolved in EtOH (10OmL), potassium thioacetate (1.8g, l ⁇ mmol) was added and the 0 reaction mixture was heated to 7O 0 C and maintained at the same temperature for 3 hours.
  • reaction mixture was stirred at room temperature for 4 hours. Subsequently it was diluted with water (40OmL) and extracted with EtOAc (1 x 20OmL, 2 x 10OmL); the combined organic layers were washed with brine solution (10OmL), dried over
  • GI 50 , TGI and LC 5 0 values using five concentrations for each compound.
  • the cell lines are maintained in DMEM containing 10% fetal bovine serum.
  • 96 well micro titer plates are inoculated with cells in 100 ⁇ L for 24 hours at 37°C, 5% CO 2 , 95% air and 100% relative humidity.
  • Each plate contains one of the above cell lines and the following in triplicate: five different concentrations (0.01, 0.1, 1, 10 and 100 ⁇ M) of four different compounds, appropriate dilutions of a cytotoxic standard and,control (untreated) wells.
  • Compounds are dissolved in DMSO to make 20 niM stock solutions on the day of drug addition and frozen at -2O 0 C. Serial dilutions of these 20 mM stock solutions are made in complete
  • T 0 measurement 24 hours after seeding the cells, 10 ⁇ L of 3-(4,5-Dimethyl- 2-thiazolyl)-2,5-diphenyl-2H-tetrazolium (MTT) solution per well is added and incubation carried out for 3 hours at 37°C, 5% CO 2 , 95% air and 100% relative humidity, protected from light. Cells incubated with compounds for 48 hours are 30 treated similarly except with the addition of 20 ⁇ L MTT solution per well and a subsequent incubation under the same conditions. After 3 hours of MTT incubation, well contents are aspirated carefully followed by addition of 150 ⁇ L DMSO per well. Plates are agitated to ensure solution of the formazan crystals in DMSO and absorbance read at 570 nm.
  • MTT 3-(4,5-Dimethyl- 2-thiazolyl)-2,5-diphenyl-2H-tetrazolium
  • GI 50 is the concentration required to decrease growth by 50%; TGI is the concentration required to decrease growth by 100% and LC50 is the concentration required to decrease growth by 50%.
  • HDAC Histone Deacetylase
  • the fluorometric assay provides a fast and fluorescence based method that eliminates radioactivity, extractions or chromatography, as used in traditional assays.
  • the assay is based on two steps. First, the HDAC fluorometric substrate, which comprises an acetylated lysine side chain, is incubated with a sample containing HDAC activity (Mouse Liver Extract). Deacetylation of the substrate sensitizes the substrate, in the second step; treatment with the Trypsin stop solution produces a fluorophore that can be easily analyzed using fluorescence plate reader.
  • Assay was done in 96 well black microplate and total volume of the assay is 100 ⁇ L.
  • Mouse liver enzyme is diluted 1:6 with HDAC buffer.
  • Enzyme cocktail is made of 10 ⁇ L of diluted enzyme and 30 ⁇ L of HDAC buffer. 40 ⁇ L of enzyme cocktail is dispensed into each well. 10 ⁇ L of different concentrations of inhibitor is added into each well, except enzyme control well. Preincubated the plate at 30 0 C for 5 minutes.
  • the HDAC reaction is started by adding 50 ⁇ L of HDAC substrate (Boc- Lys(Ac)-AMC Substrate) solution. Incubated the plate at 30 0 C for 30 minutes. Adding 100 ⁇ L of Trypsin stop solution stops the reaction.
  • the plate is incubated again at 30 0 C for 20-30 minutes.
  • the release of AMC is monitored by measuring the fluorescence at an excitation wavelength of 365 or 360 nm and Emission wavelength of 440 or 460 nm. Buffer and substrate alone kept for blank subtraction. (Dennis Wegener et, al., Anal. Biochem, 321, 2003, 202-208).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des nouveaux composés répondant à la formule générale (I), ayant une activité enzymatique inhibitrice de l'histone désacétylase (HDAC), leurs dérivés, analogues, formes tautomères, stéréoisomères, polymorphes, hydrates, solvates, les sels et compositions, les métabolites et promédicaments pharmaceutiquement acceptables de ceux-ci. La présente invention concerne plus particulièrement des nouveaux composés répondant à la formule générale (I). La présente invention concerne également un procédé de traitement du cancer, du psoriasis, des états prolifératifs et des états régulés par l'HDAC, chez un mammifère comprenant l'administration d'une quantité efficace d'un nouveau composé répondant à la formule (I) tel que décrit ci-dessus.
PCT/IB2007/000853 2006-04-05 2007-04-03 Nouveaux inhibiteurs d'hdac Ceased WO2007113644A2 (fr)

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IN629/CHE/2006 2006-04-05
IN629CH2006 2006-04-05

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WO2007113644A2 true WO2007113644A2 (fr) 2007-10-11
WO2007113644A3 WO2007113644A3 (fr) 2009-06-04

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Cited By (1)

* Cited by examiner, † Cited by third party
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KR101384350B1 (ko) * 2012-06-21 2014-04-14 충북대학교 산학협력단 히스톤 디아세틸라제 저해 활성을 갖는 신규한 히드록삼산 및 이를 유효성분으로 포함하는 항암용 조성물

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